Clinical and pharmacodynamic activity of bortezomib and decitabine in acute myeloid leukemia.

Blood
William BlumGuido Marcucci

Abstract

We recently reported promising clinical activity for a 10-day regimen of decitabine in older AML patients; high miR-29b expression associated with clinical response. Subsequent preclinical studies with bortezomib in AML cells have shown drug-induced miR-29b up-regulation, resulting in loss of transcriptional activation for several genes relevant to myeloid leukemogenesis, including DNA methyltransferases and receptor tyrosine kinases. Thus, a phase 1 trial of bortezomib and decitabine was developed. Nineteen poor-risk AML patients (median age 70 years; range, 32-84 years) enrolled. Induction with decitabine (20 mg/m(2) intravenously on days 1-10) plus bortezomib (escalated up to the target 1.3 mg/m(2) on days 5, 8, 12, and 15) was tolerable, but bortezomib-related neuropathy developed after repetitive cycles. Of previously untreated patients (age ≥ 65 years), 5 of 10 had CR (complete remission, n = 4) or incomplete CR (CRi, n = 1); 7 of 19 overall had CR/CRi. Pharmacodynamic analysis showed FLT3 down-regulation on day 26 of cycle 1 (P = .02). Additional mechanistic studies showed that FLT3 down-regulation was due to bortezomib-induced miR-29b up-regulation; this led to SP1 down-regulation and destruction of the SP1/NF-κB comple...Continue Reading

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Citations

Oct 22, 2013·Leukemia Research·Jane L LiesveldGordon L Phillips
Oct 20, 2012·Current Opinion in Oncology·Ramiro Garzon, Guido Marcucci
Sep 28, 2012·Current Opinion in Oncology·Gail J Roboz
Jan 22, 2013·Current Opinion in Hematology·Sumithira Vasu, William Blum
Nov 20, 2013·Leukemia·R Itzykson, P Fenaux
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Mar 28, 2013·Journal of Drug Delivery·Eleftheria Hatzimichael, Tim Crook
Mar 5, 2014·The Journal of Clinical Investigation·Houda AlachkarGuido Marcucci
Apr 17, 2014·Science Signaling·Ann-Kathrin EisfeldAlbert de la Chapelle
Mar 16, 2013·Clinical Cancer Research : an Official Journal of the American Association for Cancer Research·Xiaomeng HuangGuido Marcucci
Jan 20, 2016·Leukemia & Lymphoma·Alison R WalkerGuido Marcucci
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Feb 20, 2016·Blood·Guido Marcucci, Ling Li
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Feb 2, 2017·Current Treatment Options in Oncology·Xavier Thomas, Caroline Le Jeune

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